The need for new chemical agents that can modulate protein function in vivo provides a fundamental challenge for chemists. Molecules that are intermediate in size between small molecule drugs (<600 Daltons) and protein therapeutics could provide new chemical entities capable of binding to the large, flat protein surfaces required to modulate a protein function. Bis-peptides potentially could meet this need, but to date synthetic methods for preparing such compounds have not been fully explored or developed, particularly with respect to bis-peptides that contain one or more functional groups that project in defined three dimensional constellations.
Bis-peptides are analogues of peptides, but are derived from bis-amino acids bearing two carboxyl groups and two amino groups. The connection of specific bis-amino acids leads to the formation of bis-peptides with well-defined molecular shapes, which are of great interest for designing nano-structures. Bis-peptides may be spiro-cyclic oligomers or polymers assembled from stereochemically pure, cyclic bis-amino acids. Such bis-amino acids display two alpha-amino acid groups mounted on a cyclic core. In the assembly of bis-peptides, diketopiperazine rings are formed between adjacent monomers to create spiro-ladder oligomers with well-defined three-dimensional structures. The potential advantage of bis-peptides is that the relative position of each monomer's functional group is defined by the monomer's ring structure and stereochemistry in relation to its two immediate neighbors. This is in contrast to proteins, DNA, RNA and unnatural foldamers in which each monomer is joined to its neighbors by one bond and they adopt well-defined three dimensional structures in which monomers interact through many weak non-covalent interactions only after a complex, cooperative folding process that is challenging to accurately model and the outcome of which is difficult to predict.